Depression is one of the most important health care problems, especially in developed countries. At some time in their lives, about 5-10% of the population goes through a major depressive illness while minor depressive episodes may affect 25% or more of the population. The World Health Organisation has estimated that depression causes more global distress than any other illness.
Depression seriously disrupts people's lives, rendering existence both at home and at work difficult. Depression is the commonest reason for suicide. Depression is also associated with other illnesses, particularly cardiovascular diseases. People with a history of major depression were over four times more likely to have a myocardial infarction than normal individuals, even after allowing for known coronary disease risk factors (L A Pratt et al, Circulation 1996; 3123-3129). After a myocardial infarction, people with major depression are 3.5 times more likely to die than those who are not depressed (N Frasure-Smith et al, JAMA 1993; 1819-1825). There is therefore a particular need for effective treatments for depression which may be applied in particular to people with cardiovascular problems.
Depression has been treated in recent years usually by the combination of antidepressants selected from one of three major groups of compounds. These are the tricyclic and tetracyclic antidepressants and related compounds ("tricyclics"); the monoamine oxidase inhibitors (MAOIs); and the selective or partially selective serotonin uptake inhibitors (SRIs). The tricyclics have many and complex mechanisms of action, and are associated with many side effects, including cardiovascular side effects and toxicity such that they can be used for suicide attempts. The MAOIs inhibit one of the main enzymes involved in the degradation of catecholamines and also can have many side effects. Both the tricyclics and the MAOIs must be used with great caution in patients with cardiovascular disease. The SRIs have a relatively more selective action in inhibiting the reuptake of serotonin by nerve terminals and usually have fewer side effects than the other groups. However, almost as many patients on the new SRI antidepressants drop out of clinical studies due to adverse events as did with the older tricyclic drugs (K R Abrams, British Medical Journal, 1998; 316: 1183-4). Very recently, a further group of compounds known as noradrenaline reuptake inhibitors (NRIs), which constitute a new class of antidepressants, have been approved for general chemical use.
Although all four classes of antidepressants undoubtedly work, many patients fail to respond. For example, 30-40% of patients fail to respond to tricyclics (R J Bielski and R O Friedel, Archives of General Psychiatry 1976; 33: 1479-89). Failure rates with the MAOIs are similar or greater. Even the new SRIs are only modestly effective with as many as 40% of patients failing to respond in well controlled trials (e.g. S P Roose et al JAMA 1998; 279: 287-291). There is therefore a major need to improve the treatment of depression in view of its high personal and economic cost, both to the individual and to the society, particularly for patients with or at risk of cardiovascular disease. This improvement should include both better efficacy and reduced risk of adverse events.
Folic acid is an essential B group vitamin. Its Recommended Daily Allowance (RDA) in the USA is 200 microg for men and 180 microg for women. Women expecting to conceive are now recommended to take 400 microg/day in order to reduce the risk of spina bifida.
Folic acid is found in a number of natural forms which have pteroylglutamic acid as their common structure. In the gut wall, these are converted to methyltetrahydrofolic acid (MTHF) which is the main form of the vitamin in the blood. MTHF has a range of biological actions, but the most important is probably its interaction with homocysteine. Under the influence of the enzyme MTHF reductase, MTHF donates a methyl group to homocysteine in order to convert it to methionine which can then be used in a wide range of important methylation reactions. In the presence of inadequate supplies of folic acid, homocysteine levels become elevated. Homocysteine is associated with cardiovascular toxicity and there is increasing evidence that low folate levels may lead to elevated homocysteine levels which in turn lead to myocardial infarction and other forms of cardiovascular pathology (P Verhoef et al, Current Opinion in Lipidology 1998; 9: 17-22). Recent evidence suggests that homocysteine levels fall to a stable level in many people only at folic acid intakes of 400 microg/day or more (J Selhub et al, Journal of Nutrition, 1996; 126: 12585-655): P Verhoef et al, American Journal of Epidemiology 1996; 143: 845-59). The Recommended Daily Allowance may therefore be rather too low, especially for those at risk of cardiovascular disease.
This is likely to be particularly true of those individuals who carry a common mutation for the MTHF reductase gene. This is associated with somewhat reduced enzyme activity and a higher requirement for folate. The genetic variant is common, with European, American and Asian populations having prevalence rates for the homozygous mutation of 8-15%. Thus, a substantial proportion of the population is likely to require higher levels of folate than previously thought (P Verhoef et al, Current Opinion in Lipidology 1998; 9: 17-22: S S Kang et al, Circulation 1993; 88: 1463-9: P Frosst et al, Nature Genetics 1995; 10: 111-113).
Subnormal intakes and/or blood levels of folic acid have long been known to be associated with depression, although it is not clear whether this association is causal or not (T Bottiglieri, Nutrition Reviews 1996; 54: 382-290: J E Alpert and M Fava, Nutrition Reviews 1997; 55: 145-9). Most depressed people have reduced appetite and eat inadequately and so it is possible that depression in some individuals might cause folate deficiency. A possible mechanism whereby folate deficiency could cause depression is the influence of folate on the synthesis and release of neurotransmitters, particularly serotonin, but also including noradrenaline and dopamine. In animals made folate deficient, there is reduced brain serotonin synthesis (M Botez et al Nature 1979; 278: 182-3). The same paper showed that there is a window of folate intake within which serotonin synthesis is optimum. Increased amounts of folate as well as folate deficiency both suppressed the production of brain serotonin. Finding that window in humans where folic acid is effective but not toxic is important.
Based on some of the earlier work, Coppen suggested that the addition of folic acid might enhance the effects of tricyclics and MAOIs and lithium (A J Coppen, UK Patent Application GB 2072504A, 1980). Coppen pointed out that in view of the work of Botez et al, both too low and too much folic acid might be associated with depression. He therefore emphasised that too much folic acid should not be given and on these grounds in his patent specification he claimed combinations of tricyclics, MAOIs or lithium with amounts of folic acid which were above 100 microg/day but below 300 microg/day. Higher amounts were specifically excluded because of the possibility of adverse effects.
As far as we are aware, only two studies have been published in which folic acid was investigated in a placebo-controlled trial as an adjunct to antidepressive treatment as suggested by Coppen. One of these, by Coppen himself, compared the effects of 200 microg/day folic acid of placebo as an adjunct to lithium in the prevention (not the treatment) of depression. There was a small reduction in the Beck depression scale in the folate, but not the placebo group, although the difference between the groups was not statistically significant (A J Coppen et al, Journal of Affective Disorders, 1986; 10: 9-13).
The other study researched the effect of MTHF administered at very high doses (15,000-90,000 microg/day) with the concomitant administration of any other antidepressant. In that study, 11 patients with depression who were also being treated with tricyclics or lithium were given 15,000 microg/day of MTHF, while 13 patients who were being treated with tricyclics or MAOIs were given placebo. After 3 and 6 months, the improvement in the folic acid group was greater than that of placebo. However, in the folic acid group, both serum and red cell folate concentrations were above the upper limit of the assay, suggesting that this dose of MTHF was excessive and possibly dangerous (P S A Godfrey et al, Lancet 1990; 336: 392-5).
Literature research reveals other studies in which MRHF at high dosage rates has been tested for its effects in depression. In senile depression, both MTHF (50,000 microg/day) and trazodone produced small (around 15%) reductions in depression as measured by the Hamilton Depression Rating Scale (HDRS). In an open study in elderly patients, 50,000 microg/day was associated with a substantial improvement in depression, but without a placebo it is impossible to assess the validity of this effect (G P Guaraldi et al, Annals of Clinical Psychiatry 1993; 5: 101-5). In alcoholics with depression, 90,000 microg/day of MTHF also produced a reduction in depression in an open study (C Di Palma et al, Current Therapeutic Research 1994; 55: 559-568).
Thus, there is no experimental evidence that folic acid itself is able to enhance the effect of any antidepressant other than lithium. Coppen's patent application mentions only lithium, the tricyclics and the MAOIs and does not describe a single SRI or NRI. It specifically advises against using amounts of folic acid in excess of 300 microg/day. There is evidence that too much folic acid may inhibit zinc absorption and in some individuals precipitate epilepsy (D A Bender, Nutritional Biochemistry of the Vitamins, Cambridge University Press, 1992). All other treatment studies have used MTHF at doses of 15,000 microg/day or more. Only one of these (P S A Godfrey et al cited above) involved both tricyclics and MAOIs.
In view of the recent work on requirements for folate, particularly in people with the common variant MTHFR enzyme, it seemed to us that Coppen might not have been correct in emphasising that intakes of folic acid above 300 microg/day were not indicated as adjuvants to antidepressant therapy. Equally, the adverse effects of high folic acid intakes in animals, and the fact that 15,000 microg/day MTHF in humans produces blood folates levels above the limits of the assay, indicate that the very high levels used in most MTHF studies were too much. We therefore felt that there was a reason for seeing whether a folate intake above 300 microg/day, but well below 15,000 microg/day might have beneficial effects in the management of depression, and particularly on the management of depression with SRIs. Because of their relative safety and reasonable efficacy, SRIs have now become the "gold standard" for depression treatment in developed countries. There is some evidence that depressed people who fail to respond to SRIs may have low folate levels (M Fava et al, American Journal of Psychiatry 1997; 154: 426-8). However, only five out of 213 depressed patients were clearly deficient in folate and all five responded to treatment with the SRI fluoxetine, indicating that there is no simple relationship between folic acid deficiency and depression. The authors state "Our findings of an association between low folate level and both melancholic depression and poorer response to antidepressant treatment do not imply causality, however, and are somewhat limited by the potential for confounding relating to the study design".